We are seeking to identify and understand how individual genes interactively contribute to complex behavioral and personality traits in humans. A major emphasis is on cigarette smoking, the major preventable cause of cancer and all premature morbidity and mortality in the United States. The long-term aim is to develop better methods for behavioral intervention. Behavioral genetic studies of twins and adoptees have shown that many individual differences in humans, including cigarette smoking, are significantly influenced by heredity. Specifically, it has been found that the heritability for current cigarette smoking is 53%, and that the genetic influences on smoking initiation and persistence are largely independent of one another. Psychometric research suggests that some of these genetic factors influence general addictive personality traits whereas others play a direct role in nicotine sensitivity. We are seeking to identify such genes through DNA linkage and allelic association studies. Toward this end, we are collecting behavioral data, personality test scores and DNA samples from a series of never smokers, current smokers, and former smokers. Our current database consists of over 2,000 subjects, most of whom are siblings. The sib-pair design allows us to analyze genotype-phenotype correlations by both population- and family-based methodologies. In addition, we are collaborators on a clinical trial of a new smoking cessation drug. This trial involves 600 smokers who will be followed for a period of one year. In terms of addictive personality genes, we have focused on genes involved in monoamine metabolism and signaling. We previously found and replicated an association between a functional upstream regulatory region polymorphism in the serotonin transporter gene with the personality trait of neuroticism, which previous research has shown to be correlated with the persistence of addictive behaviors. Recently we have shown that there is an interaction between this polymoprhism and neuroticism for smoking cessation. Individuals with both a poorly expressed allele of the gene and high levels of neuroticism had the most difficulty in quitting smoking. We also found, in a follow-up to a study by C. Lerman and colleagues, an association between a polymoprhism in the dopamine transporter gene and smoking behavior. Dopamine is known to be a key modulator of the reinforcing effects of nicotine. In terms of nicotine sensitivity, we have focused on the gene for the beta-2 nicotinic receptor, which participates in over 90% of the high affinity nicotine-binding sites in the brain. The complete structure of the human gene has been determined, and five different single nucleotide polymorphisms (SNPs) have been identified; one of these changes an amino acid whereas four are in non-coding regions. The association of these polymorphisms with smoking behavior and nicotine sensitivity is under investigation. This Section also studies the role of genetic and epigentic differences in personality traits, sexual orientation, and other complex aspects of human behavior that play a role in human health and disease.